Culture-positive invasive aspergillosis in a medical center in Taiwan, 2000-2009.

We reviewed 776 patients who were culture positive for Aspergillus species at the hospital from 2000 to 2009. The isolates were collected for species identification by oligonucleotide hybridization and sequence analysis. A total of 96 cases of proven or probable IA were identified according to published criteria. The incidence of IA has increased significantly during the study period. Aspergillus fumigatus and A. flavus (41.7% each) were equally prevalent causative species. IA due to unusual species including A. nidulans (n=2), A. versicolor (n=2), and A. tubingensis (n=1) were also found. Among patients with IA, 55.2% had hematological disorder, 19.8% had underlying lung disorder, and 10.4% had autoimmune disease. The isolates species (P<0.001) and underlying disease (P<0.001) significantly affect the association of a positive culture with invasive disease. The overall mortality at three months was 62.5%, which remained stable throughout the study period. Multivariate analysis identified prior steroid use (P=0.007) as a significant risk factor for death, while surgery (P=0.030) and voriconazole (P=0.012) had protective effects. In conclusion, autoimmune disorders and underlying pulmonary diseases should also be considered as important predisposing factors of IA. Further emphasis on surgery and voriconazole in the management of IA might be beneficial.

Correlation between antimicrobial consumption and resistance among Staphylococcus aureus and enterococci causing healthcare-associated infections at a university hospital in Taiwan from 2000 to 2009.

This study investigated the correlation between antibiotic consumption and resistance among Staphylococcus aureus and enterococci causing healthcare-associated infections at a university hospital in Taiwan from 2000 to 2009. Overall, the trend of total consumption (defined daily dose [DDD] per 1,000 patient-days) of glycopeptides, including vancomycin and teicoplanin, significantly increased during 2000 to 2003 and remained stable during 2004-2009. Vancomycin consumption significantly increased during 2003 and decreased after 2004. A significant decrease in the resistance rate with time was found for oxacillin- and gentamicin-resistant S. aureus. In contrast, the rates of vancomycin- and teicoplanin-resistant enterocci increased significantly. A significant correlation was found between the increased use of extended-spectrum cephalosporins, ß-lactam-ß-lactamase inhibitor combinations, carbapenems and the decreased prevalence of methicillin-resistant S. aureus (MRSA). In contrast, the increased use of teicoplanin, extended-spectrum cephalosporins, ß-lactam-ß-lactamase inhibitor combinations, and carbapenems was correlated with the increased prevalence of vancomycin-resistant enterococci (VRE). In conclusion, this 10-year study in a single institution identified different correlations between the prescription of antibiotics and the resistance rates of MRSA and VRE. Strict implementation of infection control policy based on these correlates would be helpful in decreasing the presence of these multidrug-resistant pathogens in hospitals.

In vitro activity of nemonoxacin, tigecycline, and other antimicrobial agents against Helicobacter pylori isolates in Taiwan, 1998-2007.

The minimum inhibitory concentrations (MICs) of 330 nonduplicate Helicobacter pylori isolates to nemonoxacin, tigecycline, and eight other antimicrobial agents were determined by using the agar dilution method. Sequencing the quinolone resistance-determining regions (QRDRs) in the gyrA gene of these isolates was also performed. Resistance to clarithromycin showed an increasing trend during the ten-year study period and was highest (38%) in 2005. Tigecycline had potent in vitro activities against all isolates, with an MIC(90) of 0.06 µg/ml. Among the quinolones tested, nemonoxacin (MIC(50) of 0.12 µg/ml and MIC(90) of 0.25 µg/ml) and gemifloxacin had one to two-fold better in vitro activities than ciprofloxacin, levofloxacin, and moxifloxacin. Among the nine isolates (2.7%) with levofloxacin resistance, four (44.4%) were also resistant to metronidazole, three (33.3%) to clarithromycin, and two (22.2%) to amoxicillin. Isolates with levofloxacin resistance exhibited one or two of three amino acid alterations (Ser-70, Asn-87, and Asp-91) involved in QRDRs in the gyrA gene. A double mutation at Ser70Cys and Asn87Ile had a higher level of resistance. The results of this study suggest a potentially useful role of nemonoxacin and tigecycline in the treatment of infections caused by H. pylori. The gyrA mutation at Ser-70 is a novel finding and has an impact on levofloxacin resistance.

Mass psychogenic illness in nationwide in-school vaccination for pandemic influenza A(H1N1) 2009, Taiwan, November 2009-January 2010.

From 16 November 2009 to 22 January 2010, Taiwan investigated 23 clusters of mass psychogenic illness after vaccination (MPIV) in the nationwide in-school vaccination programme against the 2009 pandemic influenza A(H1N1). The median age of the 350 ill students (68% female) was 13 years. Intense media coverage of these events has driven public concerns about the safety of the pandemic influenza vaccine. In the future, countries should incorporate surveillance and communication strategies for MPIV in their pandemic preparedness plans.

Accuracy of the funnel technique of thoracic pedicle screws insertion in scoliosis surgery--an evaluation by CT-scans.

Pedicle screw system has increasingly been used for correction of thoracic scoliosis. It offers several biomechanical advantages over hook system as it controls all three-column of the spine with enhanced stability. Of many techniques of pedicle screw placement in the thoracic spine, the funnel technique has been used in Sarawak General Hospital since 2002. This prospective study aims to assess the accuracy of the placement of thoracic pedicle screws using the funnel technique in the corrective surgery of idiopathic scoliosis. A total of 88 thoracic pedicle screws were inserted into the T4 to T12 vertebrae of 11 patients. Post-operative CT-scan was performed to evaluate the position of the pedicle screw. Seventy six (86.4%) screws were noted to be totally within the pedicle. There was no screw with medial violation of the pedicle, 8 (9.1%) screws breeching the lateral wall of the pedicle and 4 (4.5%) screws with anterior and lateral penetration of the vertebral body. No clinical sequel with the mal-positioned screws was noted. In conclusion, the funnel technique enabled simple, accurate and reliable insertion of pedicle screw even in the scoliotic thoracic spine without the need of any imaging guidance. It is however imperative for the surgeon to have a thorough knowledge of the thoracic spine anatomy, and to be familiar with the technique to insert these screws diligently.

Lipobeads: a hydrogel anchored lipid vesicle system.

A new vesicle system is described that combines complementary properties of liposomes and polymeric beads. 'Lipobeads' consist of a lipid bilayer shell anchored on the surface of a hydrogel polymer cores which acts like a cytoskeleton. Anchoring is provided by fatty acids covalently attached to the surface of the hydrogel. These hydrophobic chains drive spontaneous assembly of a lipid bilayer shell around the modified hydrogel bead when exposed to a suspension of liposomes. The bilayer is stable and acts as a permeability barrier to compound loaded by prior absorption into the polymer core. Lipid mobility in the shell is similar to that found in other unanchored lipid bilayers. The system has potential application in drug delivery and for functional reconstitution of membrane proteins.

Diphtheria, tetanus and whole cell pertussis vaccine combined with hepatitis B vaccines: a comparison of two doses (10 microg and 5 microg).

BACKGROUND: A combined diphtheria-tetanus-whole cell pertussis-hepatitis B (DTPwHB) vaccine might facilitate the achievement of universal vaccination of infants against hepatitis B. METHODS: A double blind, randomized, two-armed, single center study was undertaken to evaluate the immunogenicity and reactogenicity of combined tetravalent DTPwHB vaccine, with two dosages of hepatitis B component (10 microg and 5 microg). The combined vaccine was tested in the context of a simplified vaccination schedule at 1.5, 3.5 and 6 months of age, to 120 healthy infants born to hepatitis B surface antigen-negative mothers after priming with one dose of hepatitis B vaccine (10 microg) at birth. Antibodies to each antigenic component were measured from blood samples collected immediately after birth, pre- and postvaccination blood samples. RESULTS: The reactogenicity profiles were similar in the two groups. No serious adverse events were reported. One month after completion of the four-dose vaccination schedule, all subjects except one in Group 1 (10 microg) had protective titers of anti-HBs (10 mIU/ml). At this time the geometric mean titer in Group 1 (10 microg) was higher than that observed in Group 2 (5 microg), 696 vs. 488 mIU/ml (P = 0.19). One month after three doses all subjects in both groups had protective antidiphtheria titers and antitetanus titers. The vaccine response rate to the Bordetella pertussis component of the vaccine was 88.0% in Group 1 and 96.2% in Group 2 (P = 0.86). CONCLUSION: Both combined tetravalent vaccines are safe and immunogenic when administered to infants born to a hepatitis B surface antigen-negative mother, with a 10-microg dose of priming hepatitis B vaccine at birth. This combined tetravalent DTPwHB vaccine may play an important role to promote integration of HB vaccine into the Expanded Program of Immunization in hepatitis B-endemic areas.

Local massage after vaccination enhances the immunogenicity of diphtheria-tetanus-pertussis vaccine.

The effect of local massage on adverse reactions and immunogenicity of diphtheria-tetanus-pertussis vaccine was investigated. After diphtheria-tetanus-pertussis vaccination 327 infants were either massaged or not, and adverse reactions were evaluated. Local pain and fever were more frequent in the massage group. The extra febrile episodes from massage were mild (38-39 degrees C). For evaluation of the antibody responses, 124 infants were recruited into massage or nonmassage cohorts and antibody production was measured at 2, 6, 7, 18 and 19 months of age, respectively. Subjects in the massage group developed significantly higher antibodies against filamentous hemagglutinin at 6 and 7 months of age, pertussis toxin at 6, 7, 18 and 19 months of age, pertussis agglutinogen at 18 and 19 months of age and those in the nonmassage group. Local massage after diphtheria-tetanus-pertussis vaccination was associated with better immunogenicity and more adverse reactions, including low grade fever and local pain, which were mild and not particularly disturbing.

Long term immune response of universal hepatitis B vaccination in infancy: a community-based study in Taiwan.

OBJECTIVES: To evaluate the long term immunity provided by a universal hepatitis B vaccination program in infancy and the booster effect on school age children who had no protective antibody titers to hepatitis B surface antigen. METHODS: We conducted a community-based seroepidemiologic study of 1337 healthy 7-year-old children in Taiwan one decade after the implementation of a mass hepatitis B vaccination program. A booster vaccination was suggested for noncarrier children who did not have protective titers of surface antibody. Serologic responses and infection rates were compared with those of the nonboostered children. In a nonselected group of 39 volunteer noncarrier vaccinees, quantitative serologic response was determined before, 1 month after a booster vaccination and 1 year later. RESULTS: A total of 572 children (42.8%) had low concentrations of surface antibody, and 9 were hepatitis B surface antigen carriers (0.7%). Eighty-two percent of "nonprotected" vaccinees showed immunologic memory to a booster dose and developed protective antibody titers 1 month later; 60.6% maintained protective titers 1 year later. The frequency of new hepatitis B virus infection was similar for those who received a booster and those who did not as investigated by the core antibody seroconversion during 1-year follow-up. However, the risk was low, with annual incidences of <1% in both groups, and none became chronic carriers. CONCLUSION: According to these data a universal vaccination program in infancy provides adequate protection against hepatitis B virus infection for school age children and a booster vaccination is not recommended.

Practical considerations in converting from plasma-derived to recombinant hepatitis B vaccines.

Plasma-derived and recombinant vaccines have been developed to prevent hepatitis B virus infections. Both types of vaccine perform very well with respect to safety, immunogenicity and protective efficacy. The protection afforded by both types of vaccine is satisfactory for at least 5 to 10 years after vaccination, and a further booster dose is not necessary during this period. However, the plasma-derived vaccine is costly to produce and there is an unjustified but prevalent fear that it may be contaminated by potential pathogens. The supply of human plasma for production of the plasma-derived vaccine cannot be assured once use of hepatitis B vaccines becomes universal. It is therefore inevitable that the recombinant vaccine will replace the plasma-derived vaccine. If necessary, both vaccines can be used in combination. Future directions for hepatitis B vaccine development include: determination of the need for incorporation of pre-S gene products to enhance immunogenicity; defining a practical strategy to combat the problem of escape mutants after vaccination; and development of combination vaccines containing other inactivated antigens to allow complete immunisation against several diseases with a minimal number of injections.

Outbreak of scarlet fever at a hospital day care centre: analysis of strain relatedness with phenotypic and genotypic characteristics.

An outbreak of scarlet fever involving 12 children occurred at a hospital day care centre from February to March 1996. Twenty-five throat isolates of Streptococcus pyogenes (GAS, group A streptococcus) available from 24 children, including 10 children with scarlet fever and 14 asymptomatic carriers, and one asymptomatic staff member were studied for the presence of genes encoding streptococcal pyrogenic exotoxin types A (speA), B (speB), and C (speC) and for protease activity. Antimicrobial susceptibilities using the E-test, cluster analysis by cellular fatty acid composition and random amplified polymorphic DNA (RAPD) patterns by means of arbitrarily-primed polymerase chain reaction (APPCR) of the isolates were performed to investigate the outbreak. Only one isolate from an asymptomatic child possessed the speA gene. All isolates possessed the speB gene and 24 (96%) isolates were positive for the speC gene. There was no difference in protease activity between isolates from children with scarlet fever and from asymptomatic carriers. Thirteen isolates (10 recovered from children with scarlet fever, two from asymptomatic children, and one from the staff member) were considered to be the same strain according to the identical antimicrobial susceptibility profile and RAPD patterns and were also considered to be similar by cluster analysis of fatty acid composition. These findings suggest that the outbreak was caused by a unique clone of GAS. We conclude that RAPD typing and cluster analysis by cellular fatty acids composition both provide a powerful tool for epidemiological investigation of GAS infections.

Risperidone: effects of formulations on oral bioavailability.

The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover study comparing a 1-mg tablet with a 1-mg/ml oral solution. Both formulations were administered as a single 1-mg dose with a 10-day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9-hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (Cmax, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9-hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80-120% (80-125% for log-transformed data). The results demonstrate that the 1-mg/ml oral solution and the 1-mg tablet are bioequivalent.

Hepatitis B vaccination in preterm infants.

AIM: To investigate the immunogenicity and safety of existing recommendations for hepatitis B vaccination in preterm infants. METHODS: Recombinant hepatitis B vaccine (H-B-VAX II, 5 micrograms per dose) was given to 85 preterm infants divided into two groups, using two different schedules. Forty four group A infants with birthweights of < 2000 g received three doses at 1, 2, and 7 months of age. Forty one group B infants with birthweights of > or = 2000 g received three doses at 0, 1, and 6 months of age. RESULTS: After vaccination, 42 infants from group A (95%) and 37 infants from group B (90%) developed protective levels of antibody. The final seropositive rate and the geometric mean concentration of hepatitis B surface antibody between the two groups were not significantly different. The immune response of preterm infants to hepatitis B vaccines was similar to that of term infants in a previous study. CONCLUSIONS: Preterm infants can be given hepatitis B vaccines using one of the above two different schedules, at a cutoff birthweight of 2000 g.

Novel approach to zero-order drug delivery via immobilized nonuniform drug distribution in glassy hydrogels.

A novel approach to zero-order drug delivery from glassy hydrogel matrices via an immobilized, sigmoidal, initial drug distribution has been developed. The method utilizes a controlled-extraction process on initially dry, drug-loaded hydrogels to generate an inflection-point-containing drug concentration profile followed by a vacuum freeze-drying step to rapidly remove the swelling solvent and immobilize in situ a nonuniform drug distribution. The drug release from such a system generally exhibits typical zero-order characteristics similar to that of a membrane-reservoir device. However, a saturated reservoir of active ingredient as in the membrane-reservoir device is not required because the constant release is achieved via an initially nonuniform concentration distribution instead of the constant activity in a reservoir. The applicability of the present concept and process has been demonstrated experimentally with the release of oxprenolol hydrochloride from hydrogel beads based on 2-hydroxyethyl methacrylate polymerized with a polymeric cross-linking agent.

Constant-rate drug release from novel anionic gel beads with transient composite structure.

A new anionic composite bead system with a transient membrane-matrix structure, capable of prolonged constant-rate drug release, has been developed from suspension-polymerized poly(methyl methacrylate-co-methacrylic acid) (PMMA/MAA). These composite beads have a thin PMMA/MAA surface layer and a core consisting of the sodium salt form of the polymer (PMMA/MANa). The high loading (> 20%) of a model drug (oxprenolol HCl) that is achievable in this system from a loading solution concentration as low as 0.5% suggests the formation of a drug-polymer complex in the form of an ionic salt in the core. The release of oxprenolol from such composite beads shows an initial burst effect followed by an extended constant-rate region before leveling off. Apparently, the surface PMMA/MAA layer functions as a transient rate-controlling membrane before it is completely ionized. Because the ionization process is slow, the rate-controlling characteristics of the surface layer and the resulting constant rate of drug release are both sustained for an extended period. The unique feature of the present system is not only its high drug loading capability, but also the transient nature of the rate-controlling surface layer, which is completely ionized towards the latter part of the drug release, thus avoiding prolonged tailing of drug release that is normally associated with permanent membrane-matrix systems.

Bacteremia and fungemia in hematological and oncological children with neutropenic fever: two-year study in a medical center.

A retrospective study of bacteremia in children with neutropenic fever admitted to a medical center in Taiwan from Jan. 1994 to Dec. 1995 was performed. There were in total 273 episodes of neutropenic fever during this period, but only 79 pathogens were isolated from blood specimens in 70 episodes. Klebsiella pneumoniae (27.8%), E. coli (10.1%), Staphylococcus aureus (10.1%) and Pseudomonas aeruginosa (7.6%) were the most common pathogens. All the isolates of S. aureus were methicillin sensitive. About half of K. pneumoniae (10/22) was multiple-drug resistant. There were seven infection-related mortality cases, three due to multiple-drug resistant K. pneumoniae, one due to S. aureus, one alpha-hemolytic streptococcus and two fungemia (Cryptococcus neoformans and Fusarium sp.). Vancomycin is not necessary in initial empiric therapy of neutropenic fever, while cefazolin or oxacillin may be included in cases with central venous access device. Antibiotics to cover intestinal flora, especially K. pneumoniae, are paramount in our hospital.

Clinical features of atypical Kawasaki disease.

From 1989 through 1998, a total of 132 children admitted to the National Taiwan University Hospital were identified as having Kawasaki disease. Twenty (15%) of them did not meet the diagnostic criteria of Kawasaki disease, but were considered atypical Kawasaki based on the specific clinical signs and exclusion of other causes by serologic study and culture result. The patients' age ranged from 5 months to 11 years, with a mean of 22.2 months and a median of 15 months. The male to female ratio was 1.9:1. Twenty-five percent (5/20) of them had coronary arterial lesion. No difference was found in the age distribution, sex, and rate of coronary artery involvement between typical and atypical Kawasaki disease. All patients were treated with intravenous immunoglobulin and aspirin except for 2 patients. At follow-up, patients with coronary arterial lesions had a prognosis as good as those with typical Kawasaki disease. According to these observations, atypical Kawasaki disease may be part of Kawasaki disease occurring via the same pathogenesis, but has incomplete manifestation. Clinical practitioners should have a high index of suspicion to diagnose and initiate prompt treatment to reduce the comorbidity of coronary arterial disease in patients with atypical Kawasaki disease.

Penicillin-nonsusceptible Streptococcus pneumoniae infections in children.

The emergence of penicillin-nonsusceptible Streptococcus pneumoniae (PNSSP) has brought a new clinical challenge. In Taiwan, reports of the prevalence and clinical features of PNSSP infections in children are limited. This study reviewed the resistance patterns of all clinical isolates of S. pneumoniae obtained from patients under 17 years of age from January 1993 through July 1998 in a medical center. Their clinical features and treatment responses were analyzed, with special attention paid to those patients with invasive PNSSP infections. Totally, 170 clinical isolates of S. pneumoniae were obtained from 168 patients aged under 17 years. Among those infections, there were 56 sinusitis (including 4 sinusitis with bacteremia), 44 pneumonia (including 23 pneumonia with bacteremia or empyema), 23 otitis media (including 5 otitis media with bacteremia), 9 simple bacteremia, 9 conjunctivitis, 8 meningitis, 4 peritonitis, 3 skin infections and the other 14 isolates were colonization. One hundred eleven isolates (65.3%) showed reduced penicillin susceptibility by the disk diffusion method. A trend of increasing percentiles of PRSP was noted: 27.3% (3/11) in 1993, 37.5% (9/24) in 1994, 55.5% (10/18) in 1995, 77.5% (31/40) in 1996, 66.0% (31/47) in 1997, and 87.1% (27/31) in 1998. Minimum inhibitory concentration (MIC) determinations by the E-test showed some of the isolates were intermediately resistant. Prior antibiotic usage was associated with a higher incidence of PNSSP infections. However, most children responded well to antimicrobial treatment.

Immunogenicity and safety of Haemophilus influenzae type b conjugate vaccine (HibTITER) and a combination vaccine of diphtheria, tetanus, pertussis and HibTITER (TETRAMUNE) in two-month-old infants.

A study was undertaken to evaluate the safety and immunogenicity of a combination vaccine (TETRAMUNE) of conjugate Haemophilus influenzae type b (Hib) vaccine (HibTITER) and DTP (Diphtheria, Tetanus and Pertussis) vaccine. A total of 93 healthy children were randomized to receive either TETRAMUNE (combined group), or DTP and HibTITER administered concurrently (separate group) in separate syringes at approximately 2, 4 and 6 months of age in Taiwan. Serologic responses were largely comparable between the two vaccine groups; almost all subjects were seropositive to Hib PRP (polyribosylribitol phosphate) and were protected against diphtheria and tetanus after 2 doses of vaccine and mounted prominent responses to the components of Bordetella pertussis. Subjects in the combined group did not experience more adverse reactions compared with those in the separate group. We concluded that HibTITER was highly immunogenic and safe when administered concurrently with DTP vaccine to Taiwanese children. TETRAMUNE was also safe and immunogenic and might reduce the number of injections to achieve the same protection.

Haemophilus influenzae type b meningitis with subdural effusion: a case report.

Haemophilus influenzae type b causes invasive infection in children under 2 years of age. The disease may be complicated with hearing impairment, lowered learning ability, and other neurologic sequelae. The incidence of invasive H. influenzae type b has declined dramatically after the introduction of routine administration of protein-conjugated H. influenzae type b vaccine in the United States and some other countries. Because of its low incidence in Taiwan, many clinicians are not familiar with the initial symptoms and management of H. influenzae type b. This case report describes a 7-month-old H. influenzae type b meningitis patient who had initial presentations of prolonged intermittent fever and vague neurologic signs. Left peripheral facial palsy with hearing loss in left ear and bilateral frontal subdural effusion developed during the first 5 days of cefotaxime therapy. Betamethasone was then given for 4 days to relieve the severe inflammation. Drug-induced fever was observed after 11 days of antibiotic use and subsided with prednisolone treatment. Left ear hearing impairment persisted during the follow-up period, but the children did not experience other significant development delay.